Journal of Neuroscience最新文献

Dexterous motor skills, like those needed for playing musical instruments and sports, require the somatosensory system to accurately and rapidly process somatosensory information from multiple body parts. This is challenging due to the convergence of afferent inputs from different body parts into a single neuron and the overlapping representation of neighboring body parts in the somatosensory cortices. How do trained individuals, such as pianists and athletes, manage this? Here, a series of five experiments with pianists and nonmusicians (female and male) shows that pianists have enhanced inhibitory function in the somatosensory system, which isolates the processing of somatosensory afferent inputs from each finger. This inhibitory function was assessed using a paired-pulse paradigm of somatosensory evoked potentials in electroencephalography, which measures the suppressive effect of a first stimulus [i.e., conditioning stimulus (CS)] on the response to a subsequent second stimulus. We found that pianists and nonmusicians showed an inhibitory response to the sequential stimuli to the peripheral somatosensory nerve at the wrist when the CS was intense. However, only pianists exhibited an inhibitory response to a weak CS, indicating enhanced inhibitory function in pianists. Additionally, the CS increased the information content segregating individual fingers represented in the cortical activity evoked by passive finger movements and improved the perception of fast multifinger sequential movements, specifically for pianists. Our findings provide the first evidence for experience-dependent plasticity in somatosensory inhibitory function and highlight its role in the expert motor performance of pianists.

Alpha-synuclein (αsyn) is the key pathogenic protein implicated in synucleinopathies including Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). In these diseases, αsyn is thought to spread between cells where it accumulates and induces pathology; however, mechanisms that drive its propagation or aggregation are poorly understood. We have previously reported that the small GTPase Rab27b is elevated in human PD and DLB and that it can mediate the autophagic clearance and toxicity of αsyn in a paracrine αsyn cell culture model. Here, we expanded our previous work and characterized a role for Rab27b in neuronal lysosomal processing and αsyn clearance. We found that Rab27b KD in this αsyn inducible neuronal model resulted in lysosomal dysfunction and increased αsyn levels in lysosomes. Similar lysosomal proteolytic defects and enzymatic dysfunction were observed in both primary neuronal cultures and brain lysates from male and female Rab27b knockout (KO) mice. αSyn aggregation was exacerbated in Rab27b KO neurons upon treatment with αsyn preformed fibrils. We found no changes in lysosomal counts or lysosomal pH in either model, but we did identify changes in acidic vesicle trafficking and in lysosomal enzyme maturation and localization, which may drive lysosomal dysfunction and promote αsyn aggregation. Rab27b OE enhanced lysosomal activity and reduced insoluble αsyn accumulation. Finally we found elevated Rab27b levels in human postmortem incidental Lewy Body Disease (iLBD) subjects relative to healthy controls. These data suggest a role for Rab27b in neuronal lysosomal activity and identify it as a potential therapeutic target in synucleinopathies.Significance statement Alpha-synuclein aggregation in Parkinson's disease is associated with autophagic-lysosomal dysfunction, yet the molecular mechanisms underlying alpha-synuclein clearance are not well understood. We identified the small GTPase Rab27b as a novel regulator of the lysosomal clearance of alpha-synuclein. Using several alpha-synuclein models, we found that Rab27b knockdown or knockout impairs lysosomal function, increases alpha-synuclein lysosomal accumulation, and increases alpha-synuclein aggregation. Conversely, Rab27b overexpression promotes lysosomal function and reduces alpha-synuclein aggregation. We also identified defects in lysosomal enzyme maturation and localization and acidic vesicle trafficking upon Rab27b loss, which may drive lysosomal dysfunction. These findings suggest that targeting Rab27b could boost lysosomal clearance of alpha-synuclein in synucleinopathies.

Sensory perception relies on the flexible detection and interpretation of stimuli across variable contexts, conditions, and behavioral states. The basal forebrain is a hub for behavioral state regulation, supplying dense cholinergic and GABAergic projections to various brain regions involved in sensory processing. Of GABAergic neurons in the basal forebrain, parvalbumin (PV) and somatostatin (SST) subtypes serve opposing roles towards regulating behavioral states. To elucidate the role of basal forebrain circuits in sensory-guided behavior, we investigated GABAergic signaling dynamics during odor-guided decision-making in male and female mice. We used fiber photometry to record cell type-specific basal forebrain activity during an odor discrimination task and correlated temporal patterns of PV and SST neuronal activity with olfactory task performance. We found that while both PV-expressing and SST-expressing GABAergic neurons were excited during trial initiation, PV neurons were selectively suppressed by reward whereas SST neurons were excited. Notably, chemogenetic inhibition of BF SST neurons modestly altered decision bias to favor reward-seeking while optogenetic inhibition of BF PV neurons during odor presentations improved discrimination accuracy. Together, these results suggest that the bidirectional activity of GABAergic basal forebrain neuron subtypes distinctly influence perception and decision-making during olfactory guided behavior.Significance statement This study reveals distinct roles for basal forebrain GABAergic neurons in odor perception and odor-guided decision-making. Fiber photometry shows that basal forebrain parvalbumin-expressing neurons are selectively suppressed by rewards, while somatostatin-expressing neurons are activated, establishing the unique recruitment of these GABAergic neurons during behavioral reinforcement. Chemogenetic and optogenetic interventions demonstrate divergent roles for these neuronal subtypes in reward-seeking behavior and odor perception. This research provides new insights into how GABAergic neurons in the basal forebrain shape sensory perception and decision-making.

Spontaneous neural dynamics manifest across multiple temporal and spatial scales, which are thought to be intrinsic to brain areas and exhibit hierarchical organization across the cortex. In wake, a hierarchy of timescales is thought to naturally emerge from microstructural properties, gene expression, and recurrent connections. A fundamental question is timescales' organization and changes in sleep, where physiological needs are different. Here, we describe two measures of neural timescales, obtained from broadband activity and gamma power, which display complementary properties. We leveraged intracranial electroencephalography (iEEG) in 106 human epilepsy patients (48 females) to characterize timescale changes from wake to sleep across the cortical hierarchy. We show that both broadband and gamma timescales are globally longer in sleep than in wake. While broadband timescales increase along the sensorimotor-association axis, gamma ones decrease. During sleep, slow waves can explain the increase of broadband and gamma timescales, but only broadband ones show a positive association with slow-wave density across the cortex. Finally, we characterize spatial correlations and their relationship with timescales as a proxy for spatiotemporal integration, finding high integration at long distances in wake for broadband and at short distances in sleep for gamma timescales. Our results suggest that mesoscopic neural populations possess different timescales that are shaped by anatomy and are modulated by the sleep/wake cycle.Significance statement Understanding the organization of intrinsic neural dynamics is crucial for investigating brain functions in health and disease. A key question is: how do neural dynamics change in the sleeping brain? Here we focus on neural timescales and spatial correlations. We show that two broadband and gamma timescales manifest within neural populations recorded with intracranial electroencephalography in humans. Both timescales increase in sleep but follow opposite hierarchies: broadband timescales increase from sensory to associative areas, while gamma show the reverse pattern. Finally, timescales covary with spatial correlations, suggesting higher spatiotemporal integration over long distances in wake compared to sleep.

Genetic disorders such as neurofibromatosis type 1 increase vulnerability to cognitive and behavioral disorders, such as autism spectrum disorder and attention-deficit/hyperactivity disorder. Neurofibromatosis type 1 results from mutations in the neurofibromin gene that can reduce levels of the neurofibromin protein (Nf1). While the mechanisms have yet to be fully elucidated, loss of Nf1 may alter neuronal circuit activity leading to changes in behavior and susceptibility to cognitive and behavioral comorbidities. Here we show that mutations decreasing Nf1 expression alter motor behaviors, impacting the patterning, prioritization, and behavioral state dependence in a Drosophila model of neurofibromatosis type 1. Loss of Nf1 increased spontaneous grooming in male and female flies. This followed a nonlinear spatial pattern, with Nf1 deficiency increasing grooming of certain body parts differentially, including the abdomen, head, and wings. The increase in grooming could be overridden by hunger in foraging animals, demonstrating that the Nf1 effect is plastic and internal state dependent. Stimulus-evoked grooming patterns were altered as well, suggesting that hierarchical recruitment of grooming command circuits was altered. Yet loss of Nf1 in sensory neurons and/or grooming command neurons did not alter grooming frequency, suggesting that Nf1 affects grooming via higher-order circuit alterations. Changes in grooming coincided with alterations in walking. Flies lacking Nf1 walked with increased forward velocity on a spherical treadmill, yet there was no detectable change in leg kinematics or gait. These results demonstrate that loss of Nf1 alters the patterning and prioritization of repetitive behaviors, in a state-dependent manner, without affecting low-level motor functions.Significance statement Neurofibromatosis type 1 (NF1) is associated with an increased risk of cognitive and behavioral disorders, yet the underlying neuronal mechanisms remain poorly understood. Our study utilizes a Drosophila model to demonstrate that loss of neurofibromin (Nf1) expression impacts motor behavior and the prioritization of repetitive actions, such as grooming, in a hunger state-dependent manner. Our experiments also suggest that alterations in neuronal circuit activity due to the loss of Nf1 influence behavior without impairing motor coordination. Understanding how Nf1 loss affects motor function can reveal the broader neuronal mechanisms contributing to cognitive impairment, providing valuable insights for developing therapeutic strategies.

Understanding the intricate mechanisms underlying slow-wave sleep (SWS) is crucial for deciphering the brain's role in memory consolidation and cognitive functions. It is well-established that cortical delta oscillations (0.5-4 Hz) coordinate communications among cortical, hippocampal, and thalamic regions during SWS. These delta oscillations feature periods of Up and Down states, with the latter previously thought to represent complete cortical silence; however, new evidence suggests that Down states serve important functions for information exchange during memory consolidation. The retrosplenial cortex (RSC) is pivotal for memory consolidation due to its extensive connectivity with memory-associated regions, although it remains unclear how RSC neurons engage in delta-associated consolidation processes. Here, we employed multi-channel in vivo electrophysiology to study RSC neuronal activity in freely behaving male mice during natural SWS. We discovered a discrete assembly of putative excitatory RSC neurons (∼20%) that initiated firing at SWS Down states and reached maximal firing at the Down-to-Up transitions. Therefore, we termed these RSC neurons the Down-to-Up transition Assembly (DUA), and the remaining RSC excitatory neurons as non-DUA. Compared to non-DUA, DUA neurons appear to exhibit higher firing rates, larger cell body size, and lack monosynaptic connectivity with nearby RSC neurons. Furthermore, optogenetics combined with electrophysiology revealed differential innervation of RSC excitatory neurons by memory-associated inputs. Collectively, these findings provide insight into the distinct activity patterns of RSC neuronal subpopulations during sleep and their potential role in memory processes.Significance statement Newly formed memories must undergo memory consolidation, integrating hippocampal-dependent information into pre-existing cortical networks. Recent research highlights a cortical-hippocampal-cortical loop during SWS in this process, indicating the cortex's role in initiating memory consolidation. To investigate how the RSC contributes to SWS and associated consolidation processes, we characterized a novel assembly of RSC neurons that are highly active during SWS Down states, preceding the activity of other RSC neurons during Down-to-Up transitions. We further explored how RSC neurons receive innervation from memory-associated inputs. Our findings shed light on the RSC's role in orchestrating SWS oscillations, revealing a unique assembly of cortical excitatory neurons in potentially promoting SWS Up states.

Tinnitus is the subjective perception of a sound in absence of corresponding external acoustic stimuli. Research highlights the influence of the sensorimotor system on tinnitus perception. Associated neuronal processes, however, are insufficiently understood and it remains unclear how and at which hierarchical level the sensorimotor system interacts with the tinnitus-processing auditory system. We therefore asked 23 patients suffering from chronic tinnitus (11 males) to perform specific exercises, aimed at relaxing or tensing the jaw area, which temporarily modulated tinnitus perception. Associated neuronal processes were assessed using Magnetencephalography. Results show that chronic tinnitus patients experienced their tinnitus as weaker and less annoying after completion of relaxing compared to tensing exercises. Furthermore, (1) sensorimotor alpha power and alpha-band connectivity directed from the somatosensory to the auditory cortex increased, and (2) gamma power in the auditory cortex, reduced, which (3) related to reduced tinnitus annoyance perception on a trial-by-trial basis in the relaxed state. No effects were revealed for 23 control participants without tinnitus (6 males) performing the same experiment. We conclude that the increase in directed alpha-band connectivity from somatosensory to auditory cortex is most likely reflecting the transmission of inhibition from somatosensory to auditory cortex during relaxation, where concurrently tinnitus-related gamma power reduces. We suggest that revealed neuronal processes are transferable to other tinnitus modulating systems beyond the sensorimotor one that are e.g. involved in attentional or emotional tinnitus modulation and provide deeper mechanistic insights into how and through which channels phantom sound perception might be modulated on a neuronal level.Significance Statement Tinnitus describes the perception of auditory phantom sounds. Research suggests that the sensorimotor system impacts on tinnitus perception, associated neuronal mechanisms, however, have remained unclear. Here, chronic tinnitus patients performed exercises with the jaw temporarily reducing (versus increasing) tinnitus perception. Tinnitus reduction was accompanied by an increase of alpha-band connectivity directed from the somatosensory to the auditory cortex and gamma power reduction in the auditory cortex. We suggest that the increase in alpha-band connectivity, when tinnitus is reduced, reflects the transmission of inhibition from somatosensory to auditory cortex, where, in parallel, probably tinnitus-related, gamma power reduces. The findings have important implications both for the understanding of phantom sound perception and, more generally, of top-down modulation in healthy and impaired cognition.

A growing body of evidence suggests that the link between the cardiac autonomic nervous system (ANS) and the central nervous system (CNS) is crucial to the onset and development of major depressive disorder (MDD), affecting perception, cognition, and emotional processing. The bottom-up heart-brain communication pathway plays a significant role in this process. Previous studies have shown that slow-frequency oscillations of peripheral signals (e.g., respiration, stomach) can influence faster neural activities in the CNS via phase-amplitude coupling (PAC). However, the understanding of heart-brain coupling remains limited. Additionally, while MDD patients exhibit altered brain activity patterns, little is known about how heart rate variability (HRV) affects brain oscillations. Therefore, we used PAC to investigate heart-brain coupling and its association with depression. We recorded MEG and ECG data from 55 MDD patients (35 females) and 52 healthy subjects (28 females) at rest and evaluated heart-brain PAC at a broad-band level. The results showed that the low-frequency component of HRV (HRV-LF) significantly modulated MEG alpha power (10 Hz) in humans. Compared to the healthy group, the MDD group exhibited more extensive heart-brain coupling cortical networks, including the pars triangularis. LF-alpha coupling was observed in the bilateral insula in both groups. Notably, results revealed a significantly increased sympathetic-dominated HRV-LF modulation effect on left insula alpha oscillations, along with increased depressive severity. These findings suggest that MDD patients may attempt to regulate their internal state through enhanced heart-brain modulation, striving to restore normal physiological and psychological balance.Significance Statement The afferent pathway from the heart plays a pivotal role in conveying information to the brain. This process involves the transmission of signals related to the physiological state of the heart. Our understanding of this pathway and its association with major depressive disorders (MDD) remains limited. In this study, the low-frequency component of heart rate variability (HRV-LF) was found to modulate neural activity during rest, revealing a bottom-up information transmission mechanism between the cardiac ANS and the CNS. Alterations in the LF-alpha coupling pattern were observed in patients with MDD, suggesting this as a potential neurobiological mechanism behind their altered interoception, which might affect the perception and emotional processing.

Value-based decision-making involves multiple cortical and subcortical brain areas, but the distributed nature of neurophysiological activity underlying economic choices in the human brain remains largely unexplored. Specifically, the nature of the neurophysiological representation of reward-guided choices, as well as whether they are represented in a subset of reward-related regions or in a more distributed fashion is unknown. Here, we hypothesize that reward choices, as well as choice-related computations (win probability, risk), are primarily represented in high-frequency neural activity reflecting local cortical processing, and that they are highly distributed throughout the human brain, engaging multiple brain regions. To test these hypotheses, we used intracranial recordings from multiple areas (including orbitofrontal, lateral prefrontal, parietal, cingulate cortices as well as subcortical regions such as the hippocampus and amygdala) from neurosurgical patients of both sexes playing a decision-making game. We show that high frequency activity (gamma and high-frequency activity) represents both individual choice-related computations (e.g., risk, win probability) and choice information with different prevalence and regional representation. Choice-related computations are locally and unevenly present in multiple brain regions, whereas choice information is widely distributed, more prevalent, and appears later across all regions examined. These results suggest brain-wide reward processing, with local high frequency activity reflecting the coalescence of choice-related information into a final choice, and shed light on the distributed nature of neural activity underlying economic choices in the human brain.Significance Statement Economic decision-making depends on multiple brain areas. However, how neural activity in the human brain supports choices is not well understood, due to the difficulty of measuring human neural activity. Here, we leveraged the rare opportunity to record electrophysiological activity from several human brain regions implicated in decision-making from neurosurgical patients to study the neurophysiological basis of economic decisions. We show that neural activity supporting human economic choices under uncertainty is highly distributed across brain areas. However, different relevant calculations, such as the probability of a win, or the risk of an uncertain choice, are differentially reflected in across brain regions. This study demonstrates the highly distributed, but regionally specific, nature of choices and reward computations in the human brain.

The ability to wait before responding is crucial for many cognitive functions, including reaction time tasks, where one must resist premature actions before the stimulus and respond quickly once the stimulus is presented. However, the brain regions governing waiting remain unclear. Using localized excitotoxic lesions, we investigated the roles of the motor cortex (MO) and sensorimotor dorsolateral striatum (DLS) in male rats performing a conditioned lever release task with variable delays. Neural activity in both MO and DLS showed similar firing patterns during waiting and responding periods. However, only bilateral DLS lesions caused a sustained increase in premature (anticipatory) responses, whereas bilateral MO lesions primarily prolonged reaction times. In a self-timing version of the task, where rats held a lever for a fixed delay before release, DLS lesions caused a leftward shift in response timing, leading to persistently greater premature responses. These waiting deficits were accompanied by reduced motor vigor, such as slower reward-orienting locomotion. Our findings underscore the critical role of the sensorimotor striatum in regulating waiting behavior in timing-related behaviors.Significant Statement Waiting is essential for the temporal control of actions, as many cognitive behaviors-whether stimulus-driven or internally planned-require withholding a response until the appropriate time. However, the neural substrates of waiting remain less understood. Using targeted lesions, we identified the dorsolateral striatum as a crucial region for waiting in both reaction time and self-timing tasks. Lesions in this area caused a persistent increase in premature responses across tasks. In contrast, motor cortex lesions, despite its neurons showing similar activity patterns to the striatum during waiting, did not result in a lasting increase in premature responses; instead, they led to a long-term increase in reaction time.